Project Summary Neutrophils, eosinophils and ?classical? monocytes represent a first line of defense against nearly all pathogens. Not surprisingly, these inflammatory cells are also highly prone to damaging host tissue. The lifespan of these cells is strictly regulated to balance protective immunity with immunopathology. Although, extracellular pro-survival factors are well known to influence the lifespan of these cells, how extracellular cues are translated into an optimal cellular lifespan is largely unknown. It has recently become evident that the majority of the human genome does not encode for proteins and noncoding regions are transcribed. Indeed, long noncoding RNA (lncRNA) transcripts have been demonstrated to be key controllers of gene expression. Emerging evidence indicates that lncRNAs play a critical role in translating extracellular signals into gene expression programs through histone modifications. Given the strong influence of extracellular factors on the lifespan and function of neutrophils, eosinophils and ?classical? monocytes, we postulate that lncRNAs induced by extracellular cues are critical for precisely regulating the survival of these myeloid cells. Using high-throughput sequencing, we identified a lncRNA (Gm14005) that is highly and specifically expressed by murine and human short-lived myeloid cells, and associated with human inflammatory diseases through genome wide association studies (GWAS). Deletion of this lncRNA in mice results in a profound defect in short-lived myeloid cell survival and numbers. To further test our hypothesis, we proposed the following Specific Aims: Aim 1 will utilize our lncRNA-deficient mouse model to investigate the role of Gm14005 in short-lived myeloid cell homeostasis. We will determine when during development Gm14005 controls survival, what extracellular signals regulate Gm14005 expression, and the role of Gm14005 during inflammationP Aim 2 will examine the molecular mechanism through which Gm14005 acts in vivo. Our preliminary evidence demonstrates that Gm14005-deficient short lived myeloid cells highly overexpress the neighboring pro-apoptotic gene, Bcl2l11 (Bim). Additionally, deletion of Bcl2l11 in Gm14005-deficient mice rescues short-lived myeloid numbers. We will investigate whether Gm14005 controls the histone modifications and chromatin accessibility at the Bcl2l11 locus, and whether this lncRNA interacts with repressive chromatin remodeling protein complexes. These studies will provide key insights into the fundamental but largely unknown process of how short-lived myeloid cell lifespan is tightly regulated, and function of lncRNAs in immune homeostasis. As Gm14005 is also highly and specifically expressed by human short-lived myeloid cells, these insights may aid the development of new strategies to treat human diseases characterized by dysregulated myeloid lifespan.